Chromosome 22q11.2 deletion causes PERK-dependent vulnerability in dopaminergic neurons

Abstract Background The chromosome 22q11.2 deletion is an extremely high risk genetic factor for various neuropsychiatric disorders; however, the 22q11.2 deletion-related brain pathology in humans at the cellular and molecular levels remains unclear. Methods We generated iPS cells from healthy controls (control group) and patients with 22q11.2 deletion (22DS group), and differentiated them into dopaminergic neurons. Semiquantitative proteomic analysis was performed to compare the two groups. Next, we conducted molecular, cell biological and pharmacological assays. Findings Semiquantitative proteomic analysis identified ‘protein processing in the endoplasmic reticulum (ER)’ as the most altered pathway in the 22DS group. In particular, we found a severe defect in protein kinase R-like endoplasmic reticulum kinase (PERK) expression and its activity in the 22DS group. The decreased PERK expression was also shown in the midbrain of a 22q11.2 deletion mouse model. The 22DS group showed characteristic phenotypes, including poor tolerance to ER stress, abnormal F-actin dynamics, and decrease in protein synthesis. Some of phenotypes were rescued by the pharmacological manipulation of PERK activity and phenocopied in PERK-deficient dopaminergic neurons. We lastly showed that DGCR14 was associated with reduction in PERK expression. Interpretation Our findings led us to conclude that the 22q11.2 deletion causes various vulnerabilities in dopaminergic neurons, dependent on PERK dysfunction. Funding This study was supported by the AMED under grant nos JP20dm0107087 , JP20dm0207075 , JP20ak0101113 , JP20dk0307081 , and JP18dm0207004h0005 ; the MEXT KAKENHI under grant nos. 16K19760 , 19K08015 , 18H04040 , and 18K19511 ; the Uehara Memorial Foundation under grant no. 201810122 ; and 2019 iPS Academia Japan Grant.